The invention relates to freeze-dried molded articles, containing ≧50% by wt. of one or more active substances, and ≦15% by wt. of one or more scaffold-forming agents, with proteins being excepted, as well as optionally
one or more auxiliary substances, in each case based on the total composition of the freeze-dried molded article, the 1% by wt. solution or suspension in water, at 20° C., has a pH value <7.
Furthermore, the invention relates to methods for manufacturing these freeze-dried molded articles, the combination of such freeze-dried molded articles in kit-of-parts arrangements together with aqueous solutions, as well as the use of the freeze-dried molded articles and the kit-of-parts combinations for pharmaceutical and cosmetic application.
A number of important and highly potent active substances for cosmetic and pharmaceutical application is known for being unstable and for being altered or decomposed, due to external influences, in such a way that they are no longer or no longer sufficiently capable of having the desired action in the composition in which they are contained, or that the altered active substances or their decomposed by-products even develop a harmful action. Among such unstable active substances, in particular such active substances must be mentioned in this respect which have a high degree of instability under thermal influences, as well as those that are highly susceptible to light, moisture and/or oxidation.
There is therefore a central interest in bringing such highly potent and highly unstable active substances, which are in danger of being decomposed, into a form which affords high and long-term stability, accompanied by good storability, optimal and reproducible provision of the content of active substances over the entire storage and administration period, and thus the highest possible safety and efficiency in application.
Apart from an effective stabilization of the active substances, in this context, their provision in an optimally suitable form of administration that is optimally adapted to the respective purpose of application is of particular interest. The choice of the suitable form of application in this case particularly depends on the type and place of application, the target group and its special characteristics, the type and quantity of the dosage of the active substances or their form of application, as well as, for example, the physical and biochemical characteristics of the active substances, in particular with regard to their biological availability and their systemic mode of action, which must be taken into consideration in this case.
Especially forms of application for external application as well as oral forms of application are of particular interest for providing such stable highly potent active substances in this case. In this context, in particular such forms of administration are particularly suitable and preferred for such applications, which can be used in aqueous and/or water-containing formulations or environments, and which are rapidly soluble in such aqueous environments. This is of importance in particular in the case of systems of active substances for oral application.
In order to protect biological or substances against moisture-related decomposition, deterioration or degradation, the method of freeze drying is known and widely used. In this case, the substance are frequently directly subjected to freeze drying, and the unstable active substances as such are preserved in particular in pharmaceutics. With regard to the provision of the freeze-dried, preserved active substances in suitable pharmaceutical or also cosmetic forms of application for finally applying them to or in the body, however, the problem arises of incorporating the freeze-dried and thus stabilized active substances in a stable and thus moisture-protected manner into the desired form of administration. Dry forms of application, such as powder mixtures, mixtures pressed into tablets, active substances filled into capsules or systems of active substances processed into granules are well-known. The drawbacks such application systems entail are in particular the frequently poor solubility and thus slow active substance release, the high proportion of auxiliary and filler substances, which are inactive but necessary for processing, the regularly poor suitability for external application as well as an insufficient dosability and thus unsafe handling or problems with application by the user.
A suitable and known manner of providing active substances in a form of application or dosage is to disperse the active substances in a system of carrier substances and to subject this mixture to freeze drying. Mostly, such substances are selected as carrier substances that have a good dissolution or swelling behavior and which, through swelling, enable a good texture formation, so that the dissolved active substance system, or the active substance system dispersed in the swelling agent, can be used directly as a form of application. Such systems, because of their good solubility, are known and suitable for providing oral forms of application, as well as for producing cosmetic or pharmaceutical forms of administration for external application. In this case, there in a increasing interest in providing so-called single-unit forms of application which enable a simple and precise application of a dose of an active substance for the end user. Single-unit forms of application in this context are understood to be application systems, which in contrast to powders or granules contain the desired and required quantity of active substance per application unit in a single application unit, such as tablets or capsules, without, however, having the drawbacks of poor solubility or lack of suitability for external application.
Thus, such easily soluble single-unit forms of application, which are moisture-stabilized by drying, for oral and/or external application of unstable active substances are becoming increasingly interesting in the form of larger-format embodiments, in particular if large quantities of active substances are to be administered. As a rule, the special challenge in this respect lies in providing high contents of active substances in a rapidly soluble form, and one that is soluble as completely or free of residues as possible, with as high an active substance content as possible, at as small a proportion of carrier or auxiliary substances in the composition as possible being desirable. The smaller the content in carrier or auxiliary substances, the more residue-free and more complete, as a rule, dissolution is, the smaller, however, the mechanical stability of the single molds is, as a rule, which plays a role in packaging, storing and handling in particular of large-format molded articles.
The swellable or soluble carrier substances commonly used in such forms of application are mostly selected from carrier substances which have particularly good swelling and dissolving properties in a neutral to alkaline environment, that can therefore be processed particularly well in this pH range. Moreover, for formulations to be applied externally, neutral to slightly alkaline formulations are commonly used, because those generally have a better skin compatibility and exhibit less irritation tendency. Especially for the group of acid active substances, i.e. such active substances that have a pH-dependent dissociation tendency and are therefore present in a dissociated form under neutralized or alkaline conditions, however, the problem arises that such systems can only be subjected to freeze drying in a limited extent, in particular at high contents of active substances. On the one hand, because of the high dissociation tendency of such active substances, such a high ion concentration develops in the formulation to be freeze-dried that a lowering of the freezing point of the composition occurs which renders the conditions for freeze drying unacceptably difficult. Moreover, the high ion concentration in the freeze-dried product increases its hygroscopicity to such a degree that in particular formulations with low contents of carrier substances, which have a decisive influence on the mechanical stability of the freeze-dried compositions, are not sufficiently stable. Known and important acid active substances that have the aforementioned properties, are, for example, ascorbic acid (vitamin C) and its derivatives, as well as, for example, acetylsalicylic acid (ASS) an its derivatives.
Thus, there is the necessity of providing large-format single-unit forms of application that can be dosed well, which have a high load of unstable, in particular acid active substances with a high, pH-value dependent dissociation tendency and a low content of insoluble or swellable carrier substance, and thus rapid and complete solubility and the highest possible mechanical stability for cosmetic and pharmaceutical external and oral use.
Dosable, active-substance charged pellets or single-unit drug forms of a certain size, which are supposed to make the provision of hydrolysis-sensitive active substances, such as vitamins, in particular vitamin C possible for both pharmaceutical as well as cosmetic application, are described in U.S. Pat. No. 5,405,618 and in DE4201179. The carrier materials used therein preferably are based on proteins. The pellets are produced by dripping dispersions of the protein scaffold-forming agents and optionally cosmetic or pharmaceutical active substances into cryogenic inert liquids, preferably liquid nitrogen, and subsequently separating and freeze-drying the frozen pellets. However, the presence of protein scaffold-forming agents, in particular of collagen or collagen derivatives, is necessary in order to form pellets under these conditions, because only the aforementioned protein scaffold-forming agents are able to form stable pellets under these conditions. Moreover, it is not possible to produce such molded articles with the production process described herein that have a high content of active substances and only a low content of scaffold-forming agents. Though the described method is described to be particularly suitable particularly for making hydrolysis-sensitive active substances, such as ascorbic acid (vitamin C) or acetylsalicylic acid available, however, the compositions described in the examples are all characterized by the content of scaffold-forming constituents being several times higher than the content of active substances. Thus, the method is not suitable for providing pellets with concentrations of active substances that are particularly high compared with the scaffold-forming carrier material. This is also connected with the special requirements with regard to a high-level stabilization of the composition in the dripping method used.
Similar problems result from the method for producing porous galenic particles described in U.S. Pat. No. 5,843,347, which are supposed to be obtained in sizes of up to 5 mm, according to the description. In the method used herein, a mixture of the active substances is extruded in a matrix and cut into particles with the desired size, which subsequently form the porous molded articles by freeze drying. However, the exemplary embodiments merely show that so-called microspheres with diameters of up to a maximum of 1.5 mm can be obtained. This can be ascribed to the use according to the invention of an extrusion and cutting method that requires a certain mechanical stability of the extruded mass. This can generally be obtained by a relatively high content of scaffold-forming polymers or carrier substances and stabilizers or fillers. However, if only small amounts of stabilizing carrier or auxiliary substances are used as compared with the content of active substances, then only very small-format microspheres can be obtained, as is shown in this document. The subject matter of the disclosure does not include any special possibility of stabilizing unstable, in particular so-called acid active substances.
Another method comprising the production of an emulsion containing the active substances, pouring said emulsion into a mold, and subsequent freeze drying of the emulsion, is the subject matter of WO 05/073296. According to the statements in the descriptive part, the molded articles that can be produced with this method can be obtained in sizes of 0.2-5 mm and larger, are soluble or dispersible in water, and this method is also supposed to provide a possibility of stabilizing unstable active substances, such as vitamins. However, the subject matter of the present method primarily is providing molded articles, into which the active substances are incorporated in an oil-in-wafer emulsion which additionally comprises emulsifiers, such as surfactants, in order to prepare this emulsion. However, this method also shows that the incorporation of extremely high contents of active substances at low quantities of scaffold-forming agents is not possible for reasons of stability of the large-format molded articles. Thus, the content of the scaffold-forming agents is specified to be 10 to 95% at a surfactant content of up to 5%. The example also does not offer any suggestions that the method described is suitable for producing molded articles consisting primarily of a moisture-stable, in particular acid active substance with only small amounts of stabilizing polymer. Document JP 2004-148468 describes a method for stabilizing a moisture-unstable active substance, L-ascorbic acid-2-phosphate, an ascorbic acid derivative (vitamin C derivative) by freeze drying an active substance-scaffold-forming agent-mixture while obtaining a readily soluble freeze-dried molded articles for cosmetic treatment. In this method, however, the stabilization of the active substance is achieved by using a very specific combination of scaffold-forming agents consisting of an oligosaccharide, sugar alcohol and a water-soluble polymer in specific quantity ratios. The quantity ratios show that also in this case, only such freeze-dried molded articles loaded with active substances are obtained in which the content of the stabilizing scaffold-forming agent by far exceed the content of active substances.
For both cosmetic and pharmaceutical application of single-application molded articles, relatively large molded articles of a uniform shape and size are preferred because in contrast to powders or small pellets, microspheres and granules, they can be handled more easily by the end user, so that the intention is to provide molded articles of such a size that permit a single dosage form per application. Moreover, larger molded articles, which can, for example, be given a colored design, also leave a stronger aesthetic impression.
In this context, the use of protein scaffold-forming agents is not preferred in some cases. Thus, some final increasingly prefer the use of pure plant products, in particular in cosmetics. The reasons for this result, among other things, from basic ethical considerations.
The processing of proteins moreover generally requires complicated processing and purification steps. Furthermore, the properties of the protein scaffold-forming agents in the external application on the skin are too limited with regard to their range of properties, because they are always composed of the same amino acids.
In order to obtain rapidly soluble large-format molded articles that are as completely soluble as possible with a high load of active substances as desired both in cosmetics as well as in pharmaceutical use, which in particular make the stable provision of moisture-sensitive and in particular so-called acid active substances possible, such as, for example, ascorbic acid (vitamin C) and its derivatives, or acetylsalicylic acid and its derivatives, such scaffold-forming agents of non-proteinogenic origin, such as in particular plant polymer scaffold-forming agent such as high-molecular polysaccharides, e.g. alginates or animal polyaminosaccharides, such as chitin and its derivatives, in particular chitosan, for the aforementioned reasons, are thus particularly suitable for producing such freeze-dried active-substance molded articles, also because of their solution behavior and their high gel forming capacity.
Thus, DE 10248314, which was also published as WO 2004/035023, describes large-formal molded articles of a regular shape loaded with active substances, which articles can be obtained by a freeze-drying method of an active substance-scaffold-forming agent-mixture poured into molds. The molded articles that can be obtained according to the described method are characterized by good mechanical stability and a high dissolution rate. The molded articles described can be obtained with quantities of plant scaffold-forming agents of at least 10% by wt. based on the total composition. Though amounts of 0-85% by wt. are in principle specified as possible contents of active substances, it is emphasized that loads of active substances ≦50% by wt. are being preferred. Only embodiments with up to a maximum of 25% by wt of active substance (example 4) are supported by the examples. Moreover, no suggestions are given by the document as regards a specific pH value of the molded articles disclosed therein, such as in particular a pH value <7 or even ≦6 or ≦4. Numerous groups and classes of active substances are being listed as possible active substances. No special focus on the stabilization of unstable active substances, in particular those that have a low moisture stability and a high dissociation tendency in a neutral to alkaline environment (so-called acid active substances) can be seen in this document, nor is a suggestion with regard to a stabilization of such unstable acid active substances by means of a specific pH value setting apparent. The dissolution rate of the molded articles described lies in a range of <4 minutes; it is dependent in principle on the respective content of scaffold-forming agents.
Fundamentally, such preparations having a particularly low content of scaffold-forming agents are more rapidly and completely soluble than those having a high content of scaffold-forming agents. In the case of especially large-format molded articles, in particular those based on plant scaffold-forming agents, such as alginates, and their use in a very small ratio relative to the active substance present, the problem quickly arises of obtaining sufficient mechanical stability in order to be able to produced molded articles with a regular form and rapid and complete solubility as they are required both for external applications as well as for oral application.
In particular the incorporation and stabilization of large quantities of such moisture-labile, acid active substances, such as ascorbic acid (vitamin C) and its derivatives or acetylsalicylic acid and its derivatives, which, besides their high moisture susceptibility, also have the effect of lowering the freezing point because of their dissociation tendency, is so far not possible in freeze-dried compositions, such as in the scaffold-forming agent-containing freeze-dried molded articles disclosed in DE 10248314. Due to the freezing-point lowering effect of such dissociated active substances large ice crystals with a large content of non-freezable water and high active substance concentrations or ion concentrations form in the frozen molded article, which lead to a partial structural collapse of the freeze-dried final product, to a so-called thawing of the molded article, so that the production of mechanically stable, uniform and attractive molded articles could so far not be carried out with the methods described.
DE 2017373 solves the problem of thawing of high quantifies of freezing-point lowering vitamin C in the production of mechanically stable, rapidly and completely soluble, moisture-stable, dosable pharmaceutical single-application forms by the content of freezing-point lowering vitamin C, which at approximately 30% by wt. is already unusually high, being mixed together with a quantity of approximately 70% by wt. of scaffold-forming agent and proteinogenic filler glycine after the vitamin C has previously been foamed with a synthetic block copolymer.
The use of such synthetic block copolymers, however, is not desired in cosmetic and pharmaceutical preparations because in principle, the use of synthetic substances or of carrier, auxiliary or additive substances without an actual pharmacological effect is to be kept at a minimum in order to avoid possible toxicological or pharmacological side effects. Furthermore, the addition of polymer carrier substances in principle reduce the solubility of the preparations as their content increases, which is why it is desirable to work with as small amounts as possible and to use, if possible, natural and toxicologically harmless polymer and carrier substances.
Therefore, the object of the present invention lay in providing a freeze-dried composition in which extremely high amounts of unstable, even so-called acid active substances (substances having a pKa value ≦7 at 25° C.) could be kept stabilized long-term and which could be released and applied rapidly, efficiently, specifically and highly actively during application. Moreover, another object lay in finding for these freeze-dried compositions a possibility of incorporating large quantities of such acid active substances, which in principle have a freezing-point lowering effect and which thus could not be used for the production of freeze-dried preparations so far. Moreover, the object lay in designing these stable active substance compositions in such a way that they have high mechanical strength and sufficient size in order, in particular, to be capable of being used for cosmetic or pharmaceutical application in the form of so-called single-dose units or single-dosage applications. In this case, the compositions are supposed to be equally suited for external application as well as for an oral or peroral application.
Surprisingly, it was found that, based on the above-mentioned DE 10248314 (WO 2004/035023), such stable, large-format active substance-loaded molded articles could be produced that contain quantities of active substances, which at ≧50% by wt. content of active substances and ≦15% by wt. content of scaffold-forming agents, lie in the outermost limits of DE 10248314, and in particular beyond them. Surprisingly, in particular unstable, acid active substances which, due to their freezing-point lowering effect, could not be worked into freeze-dried compositions of the present type in such large quantifies so far, can be incorporated in this case by the compositions into which the active substances are incorporated being previously adjusted to a pH value ≦7, preferably ≦6, more preferably ≦5, particularly preferably ≦4.
Freeze-dried compositions containing at least 10% by wt. of carrier materials as well as up to 50% by wt. active substances in stabilized form, preferably in the form of derivatives and/or precursors of active substances, are known from DE 102006038629. As active substances, those from the group of vitamins, such as in particular vitamin C (ascorbic acid) and derivatives are specified as being particularly preferred in this case. Moreover, the compositions contain up to 50% by wt. of an agent for forming the active substance from the stabilized form upon addition of an aqueous phase to the composition. Such releasing agents are preferably selected from the group of enzymes. However, DE 102006038629 does not offer any suggestions as to a specific pH value of the molded articles disclosed therein, such as, in particular, a pH value of <7 or even ≦6 or ≦4. Only in connection with the preferably used carrier materials from the group of the alginates is a preferred pH value of 6-8 mentioned. However, the latter only serves for characterizing the alginates used and does not make if possible to draw any conclusion as to the pH value for the molded article according to the invention that is obtained in the end.
The corresponding international application WO 2008/020066 goes beyond the disclosure of the above-mentioned DE 102006038629 in that it additionally contains the exemplary embodiments 1 to 5. In this case, examples 1 to 3 disclose the production of an appropriate freeze-dried composition, wherein the pH value is adjusted to 4-5 and wherein the obtainable compositions comprise approx. 16% by wt. carrier material and approx. 1.6% by wt. stabilized active substance (ascorbyl glucoside). In addition, approximately 82% by wt. of the enzyme glucoamylase is added to the compositions in the form of a commercially available enzyme solution (Novozym 300 GL; 10-40%) as well as, optionally, further auxiliary substances. The commercially available enzyme solution Novozym 300 GL contains 10 to 40% glucoamylase, whereby the latter can be contained in the composition in a proportion of approximately 8 to maximally 33% by wt.
Though in principle, enzymes can also develop activity as an active substance, however, in the present case enzymes are not included in the definition of the active substances which are present in particular in the form of stabilized derivatives. Glucoamylase is added to the compositions merely as a releasing agent which releases the active substance ascorbic acid upon addition of a liquid. Furthermore, a content of active substances ≧50% by wt. is not disclosed in any case by the examples 1-3 of WO 2008/020066, even taking into account the enzymes. Thus, documents DE 102006038629 and WO 2008/020066 do not disclose any freeze-dried compositions with a content of active substances ≧50 by wt. and a pH value <7 or even ≦6 or ≦4.
From FR 2 886 845, furthermore, dry compositions are known which may contain scaffold-forming agent, such as sodium alginates, in an amount of 15-75% by wt., as well as ascorbic acid in a content of 0.1-80% by wt., and which can be obtained, inter alia, by lyophilization. However, this document does not offer any concrete suggestions as to a pH value to be selected specifically, especially as the object of stabilization of the unstable active substance ascorbic acid is achieved by FR 2886845 by adding the maleic acid copolymer. Thus, this document also does not offer any suggestions as to a freeze-dried composition with a content of active substances ≧50% by wt. and a specific pH value <7 or even ≦6 or ≦4. A concrete pH value is merely specified in connection with the exemplary embodiment 1, with the composition disclosed therein not disclosing any particularly high contents of active substances ≧50% by wt. Thus, freeze-dried molded articles with a content of active substances ≧50% by wt. and a specific pH value <7 or even ≦6 or ≦4 are also not apparent from FR 2 886 845.
EP 0888769 discloses cosmetic compositions in a lyophilized form, containing 10 to 30% by wt alginates and 70 to 90% by wt. active substances, wherein plant extracts, algae extracts, minerals and trace elements as well as marine proteins, such as in particular marine collagens or marine nucleotides are specified as active substances. Active substances from the group of acid active substances are not being disclosed. Moreover, EP 0888769 also does not offer any suggestions as to a specific pH value of the compositions according to the invention, such as, in particular, a pH value <7 or even ≦6 or ≦4.
Therefore, a freeze-dried, mechanically stable, large-format active substance molded article was surprisingly obtained, which, due to the extremely low content in scaffold-forming agents according to the invention moreover could again be significantly improved with regard to its dissolution behavior as compared with the systems already known, such as those described in DE 10248314.
Moreover, it was surprisingly found that by selecting a scaffold-forming agent from the group of polyaminosaccharides, such as chitin or its derivatives, in particular by selecting chitosan as scaffold-forming agent, the stability and the dissolution behavior of such freeze-dried active substance molded articles with very low contents of scaffold-forming agents can be improved even further. This also applies to cationized starch derivatives or cationically modified carboxymethylcellulose.
To a large extent, this can be ascribed to the particularly good solubility of chitosan and cationized starch in acid pH ranges.
Neither DE 10248314 nor DE 2017373, nor any of the other documents discussed herein disclose a recipe with such low content of scaffold-forming agents, in particular selected from the group of chitin derivatives, such as chitosan or cationized starch or cationized carboxymethylcellulose and correspondingly high contents of active substances, in particular of acid, freezing-point lowering active substances, which can be incorporated by adjusting the pH value to pH ≦7, preferably pH ≦6, more preferably pH ≦5, particularly preferably pH ≦4, in order to arrive at porous, freeze-dried molded articles with the corresponding desired properties with regard to mechanical stability, dissolution behavior and size for the application in a cosmetic and pharmaceutical single-dosage application.